Ligand-controlled C(sp³)-H arylation and olefination in synthesis of unnatural chiral α-amino acids

Science. 2014 Mar 14;343(6176):1216-20. doi: 10.1126/science.1249198.

Abstract

The use of ligands to tune the reactivity and selectivity of transition metal catalysts for C(sp(3))-H bond functionalization is a central challenge in synthetic organic chemistry. Herein, we report a rare example of catalyst-controlled C(sp(3))-H arylation using pyridine and quinoline derivatives: The former promotes exclusive monoarylation, whereas the latter activates the catalyst further to achieve diarylation. Successive application of these ligands enables the sequential diarylation of a methyl group in an alanine derivative with two different aryl iodides, affording a wide range of β-Ar-β-Ar'-α-amino acids with excellent levels of diastereoselectivity (diastereomeric ratio > 20:1). Both configurations of the β-chiral center can be accessed by choosing the order in which the aryl groups are installed. The use of a quinoline derivative as a ligand also enables C(sp(3))-H olefination of a protected alanine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / chemistry
  • Alkenes / chemistry
  • Amino Acids / chemical synthesis*
  • Carbon / chemistry
  • Catalysis
  • Hydrogen Bonding
  • Ligands
  • Palladium / chemistry*
  • Pyridines / chemistry*
  • Quinolines / chemistry*
  • Stereoisomerism

Substances

  • Alkenes
  • Amino Acids
  • Ligands
  • Pyridines
  • Quinolines
  • Palladium
  • Carbon
  • Alanine